Novel antibacterial agents

ABSTRACT

This invention relates to novel macrolides, to the preparation of novel macrolides, to the use of such novel macrolides preventing, treating, or ameliorating various conditions, and to the use of such novel macrolides as antibacterial agents.

RELATED APPLICATIONS

This application claims priority from provisional applications,MACROLIDES AND PROCESSES FOR THEIR PREPARATION, Provisional PatentApplication No. 60/453,601, filed on Mar. 10, 2003 and NOVELANTIBACTERIAL AGENTS, Provisional Patent Application No: 60/468242,filed on May 6 2003.

FIELD OF THE INVENTION

This invention relates to compounds having antiviral, antibacterial,antiprotozoal, anticancer and anti-gastrointestinal therapeutic activityand to pharmaceutical compositions and methods of treatment employingthe same.

BACKGROUND OF THE INVENTION

The following background section is provided to aid in understanding theinvention, but is not admitted to be or to describe prior art to theinstant invention. All documents including patents, publications andpatent applications referred to herein are hereby incorporated byreference in their entireties.

Macrolide compounds are known to be useful in treating and preventing abroad spectrum of bacterial and protozoal infections in mammals, fishand birds and are potential agents for the treatment of gastrointestinalmotility disorders such as diabetic gastroparesis, non-ulcerativedyspepsia, irritable bowel syndrome and paralytic ileus in man.

These compounds, including derivatives of erythromycin A, are used andexhibit desirable activity against a number of Gram-positive pathogens.It is also well known that the widespread use of antibiotics over thepast 70 years has resulted in the development of a host ofantibiotic-resistant pathogens. Numerous examples of resistantinfections have been documented in both the hospital and communitysettings. The present clinically used macrolide antibiotic compounds maybe ineffective against these emerging resistant mutants. Therefore, itis of critical importance to develop and provide new drugs withbroad-spectrum activity, particularly against drug-resistant strains.

Erythromycin A is a 14-membered macrolactone with good activity againstmany Gram-positive bacteria. Resistance to this class of antibiotics hasbeen observed however, occurring by one of three mechanisms: (1)inactivation of the drug by chemical modification, (2) targetmodification such as ribosomal methylation (known as MLS_(B)) or (3) bymacrolide efflux. Furthermore Erythromycin A loses activity in acidicmedia and the decomposition products can give rise to gastricintolerance in many patients.

A second generation of macrolides, also natural products, contain a16-membered ring e.g. spiramycin, first described in 1956 (G.B. Pat. No.758,726). The 16-membered macrolides are also acid susceptible.Clarithromycin (U.S. Pat. No. 4,331,803) and azithromycin (U.S. Pat. No.4,474,768) exemplify a third generation of macrolides. They aresemi-synthetic derivatives of Erythromycin A, which overcome the problemof acid instability by preventing the formation of a 6,9-hemiketal bymethylation of the 6-hydroxyl in the case of Clarithromycin and by theconversion of the 9-ketone to a tertiary amine in the case ofAzithromycin.

Recently, a new class of macrolide compounds has been disclosed, namely,ketolides. Representative examples include telithromycin (U.S. Pat. No.5,635,485) and ABT-773 (U.S. Pat. No. 6,028,181), which are designedparticularly to combat respiratory tract pathogens that have acquiredresistance to macrolides. The ketolides are semi-synthetic derivativesof the 14-membered macrolide erythromycin A. The preparation of theseketolides is disclosed in J. Med. Chem., 2000, 43, P. 1045. CurrentMicrobiology, 2001, 42, P. 203. Bioorganic & Medicinal ChemistryLetters, 2000, 10, P. 2019. U.S. Pat. No. 6,420,535 and WO patent No.9⁹/₂1866. Ketolides are acid-stable and highly potent against mostGram-positive bacteria and do not induce MLS_(B) resistance.

However, bacterial strains resistant to existing macrolides are beingcontinually isolated and so there is an urgent need to identify newderivatives with improved activity against both Gram-positive andGram-negative organisms and with superior resistance profiles.

SUMMARY OF THE INVENTION

This invention relates to novel functionalized macrolides, to methods ofpreparing novel functionalized macrolides, to the use of such novelfunctionalized macrolides for preventing, treating, or amelioratingvarious conditions, and to the use of such novel functionalizedmacrolides as antibacterial agents.

The present invention is directed to compounds represented by StructuralFormula 1 and 2 and their pharmaceutically acceptable salts, solvates,esters, hydrates and prodrugs thereof, and methods of making, methods ofusing, and pharmaceutical compositions having compounds represented byStructural Formula 1 and Formula 2 and pharmaceutically acceptable saltsthereof, wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together areas follows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof;

Or X and Y taken together are O;

V is —C(O), —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein the firstdash of each of the foregoing V groups is attached to the C-10 carbon ofthe compounds of Formulae 1 and 2 and the last dash of each group isattached to the C-8 carbon of the compounds of Formulae 1 and 2 and R₁₁is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or taken togetheras hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyland pharmaceutically acceptable salts thereof and R₁₄ is hydrogen,hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH, S(O)₂—, S(O)₂NH—, —C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In another aspect, the present invention includes methods for removingcertain moieties, such as monosaccharide or disaccharide moieties, frommacrolide compounds, and to the further functionalization of alteredmacrolide compounds.

In yet another aspect, the present invention provides methods forremoving a sugar building block, or a substituted sugar building block,from a macrolide compound having a sugar building block, or asubstituted sugar building block as a substituent.

In yet another aspect, the present invention includes methods forsynthesizing compounds of Formula I and Formula 2, theirpharmaceutically acceptable salts, solvates, hydrates, esters orprodrugs thereof, wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof.

X is H,

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O), —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein the firstdash of each of the foregoing V groups is attached to the C-10 carbon ofthe compounds of Formulae 1 and 2 and the last dash of each group isattached to the C-8 carbon of the compounds of Formulae 1 and 2 and R₁₁is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or taken togetheras hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyland pharmaceutically acceptable salts thereof and R₁₄ is hydrogen,hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In yet another aspect, the present invention provides pharmaceuticalcompositions for the treatment of disorder(s) selected from the groupconsisting of a viral infection, bacterial infection, a protozoalinfection, or a disorder related to a bacterial infection or protozoalinfection in a mammal, fish or bird which comprises a therapeuticallyeffective amount of a compound of Formula 1 and Formula 2, theirpharmaceutically acceptable salts, hydrates, solvates, esters andprodrugs thereof and a pharmaceutically acceptable carrier, wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

wherein X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O), —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein the firstdash of each of the foregoing V groups is attached to the C-10 carbon ofthe compounds of Formulae 1 and 2 and the last dash of each group isattached to the C-8 carbon of the compounds of Formulae 1 and 2 and R₁₁is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or taken togetheras hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyland pharmaceutically acceptable salts thereof and R₁₄ is hydrogen,hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—, —C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In yet another aspect, the present invention provides a method oftreating a disorder selected from the group consisting of a viralinfection or bacterial infection, a protozoal infection, or disorderrelated to a bacterial infection or protozoal infection in a mammal,fish or bird which comprises administering through any route ofadministration, to said mammal, fish, or bird a therapeuticallyeffective amount of a compound of Formula 1 and Formula 2, theirpharmaceutically acceptable salts, hydrates, solvates, esters andprodrugs thereof and a pharmaceutically acceptable carrier, wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O), —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein the firstdash of each of the foregoing V groups is attached to the C-10 carbon ofthe compounds of Formulae 1 and 2 and the last dash of each group isattached to the C-8 carbon of the compounds of Formulae 1 and 2 and R₁₁is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or taken togetheras hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyland pharmaceutically acceptable salts thereof and R₁₄ is hydrogen,hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In yet another aspect, the present invention provides a disinfectanthaving the structure of Formula 1 and Formula 2 or their acceptablesalts, hydrates or solvates thereof, wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O)—, —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein thefirst dash of each of the foregoing V groups is attached to the C-10carbon of the compounds of Formulae 1 and 2 and the last dash of eachgroup is attached to the C-8 carbon of the compounds of Formulae 1 and 2and R₁₁ is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureylor carbamoyl and pharmaceutically acceptable salts thereof and R₁₄ ishydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—, —C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In yet another aspect, the present invention provides a pharmaceuticalcomposition for the treatment of cancer, in particular non-small celllung cancer, in a mammal, in particular a human, which comprises atherapeutically effective amount of a compound of Formula 1 and Formula2, or their pharmaceutically acceptable salts, hydrates, solvates,esters and prodrugs thereof, and their pharmaceutically acceptablecarriers, wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O)—, —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein thefirst dash of each of the foregoing V groups is attached to the C-10carbon of the compounds of Formulae 1 and 2 and the last dash of eachgroup is attached to the C-8 carbon of the compounds of Formulae 1 and 2and R₁₁ is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureylor carbamoyl and pharmaceutically acceptable salts thereof and R₁₄ ishydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—, —C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In yet another aspect, the present invention provides a method oftreating cancer, in particular non-small cell lung cancer in a mammal,in particular a human, which comprises administering to said mammal atherapeutically effective amount of a compound of Formula 1 and Formula2, or their pharmaceutically acceptable salts, hydrates, solvates,esters and prodrugs thereof, and pharmaceutically acceptable carriers,wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O)—, —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein thefirst dash of each of the foregoing V groups is attached to the C-10carbon of the compounds of Formulae 1 and 2 and the last dash of eachgroup is attached to the C-8 carbon of the compounds of Formulae 1 and 2and R₁₁ is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureylor carbamoyl and pharmaceutically acceptable salts thereof and R₁₄ ishydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

In yet another aspect, the present invention provides a method forpreventing, inhibiting, or stopping the growth of bacteria, for example,on or in a surface, which comprises applying to a surface an effectiveamount of an antibacterial agent having the structure of Formula 1 andFormula 2 or their acceptable salts, hydrates or solvates thereof,wherein:

R₁ is selected from H, cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O)—, —C(═NR₁₁)—, —C(NR₁₂,R₁₃)—, or —N(R₁₄)CH₂—, wherein thefirst dash of each of the foregoing V groups is attached to the C-10carbon of the compounds of Formulae 1 and 2 and the last dash of eachgroup is attached to the C-8 carbon of the compounds of Formulae 1 and 2and R₁₁ is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureylor carbamoyl and pharmaceutically acceptable salts thereof and R₁₄ ishydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

DETAILED DESCRIPTION OF THE INVENTION

All documents including patent, publications and patent applicationsreferred to herein are hereby incorporated by reference in theirentireties. The compounds of the present invention may be prepared, forexample, according to the schemes and examples provided below. Unlessotherwise indicated, the substituents of the compounds in the schemesare defined as described below.

The present invention provides novel classes of aglycones and,particularly, macrolide compounds of Formula 1 to which are introduced avariety of monosaccharide or oligosaccharide building blocks at 5-OHsites, rendering potential pharmaceutical agents for preventing ortreating antibacterial infections and antibiotic drug resistance.

The present invention also provides novel classes of macrolideantibiotics with the Formula 2 bearing a 1,2,3 triazole ring linked viaa spacer to 11,12 carbamate around a 14-membered macrolide corerendering potential pharmaceutical agents for preventing or treatingbacterial infections and antibiotic drug resistance.

A compound of Formula 1 and Formula 2 includes compounds having thefollowing structures or their pharmaceutically acceptable salts, estersor prodrugs thereof, and optionally including a pharmaceuticallyacceptable carrier:

wherein R₁ is selected from H, cyclic and acyclic alkyl, cyclic andacyclic alkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclicacyl, cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, acylheteroaryl,alkylheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)—NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including, a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine;

R₂ and R₃ are each independently OH, or R₂ and R₃ are taken together asfollows:

where Z is O, or —N(R₆); where R₆ is hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl,acyl, or sulfonyl, ureyl or carbamoyl and pharmaceutically acceptablesalts thereof;

X is H;

Y is OR₇; where R₇ is a monosaccharide or disaccharide (includingaminosugars or halosugars), alkyl, aryl, heteroaryl, acyl (particularly,4-nitro-phenylacetyl and 2-pyridylacetyl), or —C(O)—NR₈R₉, where R₈ andR₉ can be independently or taken together as hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamyl andpharmaceutically acceptable salts thereof,

or X and Y taken together are O;

V is —C(O)—, —C(═NR₁₁)—, —C(NR₁₂R₁₃)—, or —N(R₁₄)CH₂—, wherein the firstdash of each of the foregoing V groups is attached to the C-10 carbon ofthe compounds of Formulae 1 and 2 and the last dash of each group isattached to the C-8 carbon of the compounds of Formulae 1 and 2 and R₁₁is hydroxy or alkoxy, R₁₂ and R₁₃ can be independently or taken togetheras hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyland pharmaceutically acceptable salts thereof and R₁₄ is hydrogen,hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureyl or carbamoyl andpharmaceutically acceptable salts thereof;

W is H, F, Cl, Br, I, or OH;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; and

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl,aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl,ureyl or carbamoyl and pharmaceutically acceptable salts thereof;wherein R₁₀ is hydrogen or acyl.

Definitions

The compounds of the invention comprise asymmetrically substitutedcarbon atoms. Such asymmetrically substituted carbon atoms can result inthe compounds of the invention comprising mixtures of stereoisomers at aparticular asymmetrically substituted carbon atom or a singlestereoisomer. As a result, racemic mixtures, mixtures of diastereomers,as well as single diastereomers of the compounds of the invention areincluded in the present invention. The terms “S” and “R” configuration,as used herein, are as defined by the IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,13-30.

The term “treating” as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment” as usedherein, refers to the act of treating, as “treating” is definedimmediately above.

The compositions containing the compound(s) of the invention can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from an infection, as described above, in an amountsufficient to cure or at least partially arrest the infection and/or itssymptoms. An amount adequate to accomplish this is defined as“therapeutically effective amount or dose.” Amounts effective for thisuse will depend on the severity and course of the infection, previoustherapy, the patient's health status and response to the drugs, and thejudgment of the treating physician. In prophylactic applications,compositions containing the compounds of the invention are administeredto a patient susceptible to or otherwise at risk of a particularinfection. Such an amount is defined to be a “prophylactically effectiveamount or dose.” In this use, the precise amounts again depend on thepatient's state of health, weight, and the like.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved condition is retained.When the symptoms have been alleviated to the desired level, treatmentcan cease. Patients can, however, require intermittent treatment on along-term basis upon any recurrence of the disease symptoms.

In general, a suitable effective dose of the compound of the inventionwill be in the range of 0.1 to 5000 milligram (mg) per recipient perday, preferably in the range of 1 to 1000 mg per day, more preferably inthe range of 10 to 200 mg per day. The desired dosage is preferablypresented in one, two, three, four or more subdoses administered atappropriate intervals throughout the day. These subdoses can beadministered as unit dosage forms, for example, containing 5 to 1000 mg,preferably 10 to 100 mg of active ingredient per unit dosage form.Preferably, the compounds of the invention will be administered inamounts of between about 1.0 mg/kg to 250 mg/kg of patient body weight,between about one to four times per day.

The term “carbon chain” means a plurality of carbon atoms covalentlybonded to one another. The chain may be alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, or heteroalkynyl, aromatic, conjugated,branched, unbranched, substituted, cyclic, or combinations thereof. Ifpart of a linker and that linker comprises one or more rings as part ofthe core backbone, for purposes of calculating chain length, the “chain”only includes those carbon atoms that compose the bottom or top of agiven ring and not both, and where the top and bottom of the ring(s) arenot equivalent in length, the shorter distance shall be used indetermining chain length. As noted above, the carbon chain may alsocontain one or more heteroatoms, i.e., atoms other than carbon. If thechain contains heteroatoms as part of the backbone, those atoms are notcalculated as part of the carbon chain length.

A “pharmacological composition” or “pharmaceutical composition” refersto a mixture of one or more of the compounds described herein, orphysiologically acceptable salts thereof, with other chemicalcomponents, such as physiologically acceptable carriers and/orexcipients. The purpose of a pharmacological composition is tofacilitate administration of a compound to an organism.

“Pharmaceutically acceptable salts” of the compounds of the inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, gluconic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, 1,2ethanesulfonic acid (edisylate), galactosyl-d-gluconic acid, and thelike. Other acids, such as oxalic acid, while not themselvespharmaceutically acceptable, may be employed in the preparation of saltsuseful as intermediates in obtaining the compounds of this invention andtheir pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N-(C₁-C₄ alkyl)₄ ⁺ salts,and the like. Illustrative examples of some of these include sodiumhydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, andthe like.

A “physiologically acceptable carrier” refers to a carrier or diluentthat does not cause significant irritation to an organism and does notabrogate the biological activity and properties of the administeredcompound.

An “excipient” refers to an inert substance added to a pharmacologicalcomposition to further facilitate administration of a compound. Examplesof excipients include but are not limited to calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils and polyethylene glycols.

The term “alkyl,” alone or in combination, refers to an optionallysubstituted straight-chain, optionally substituted branched-chain, oroptionally substituted cyclic alkyl radical having from 1 to about 30carbons, more preferably 1 to 12 carbons. Examples of alkyl radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and thelike. The term “cycloalkyl” embraces cyclic configurations, is subsumedwithin the definition of alkyl and specifically refers to a monocyclic,bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein eachcyclic moiety has from 3 to about 8 carbon atoms. Examples of cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. A “lower alkyl” is a shorter alkyl, e.g., one containing from1 to about 6 carbon atoms.

The term “alkenyl,” alone or in combination, refers to an optionallysubstituted straight-chain, optionally substituted branched-chain, oroptionally substituted cyclic alkenyl hydrocarbon radical having one ormore carbon-carbon double-bonds and having from 2 to about 30 carbonatoms, more preferably 2 to about 18 carbons. Examples of alkenylradicals include ethenyl, propenyl, butenyl, 1,4-butadienyl and thelike. The term can also embrace cyclic alkenyl structures. A “lowerakenyl” refers to an alkenyl having from 2 to about 6 carbons.

The term “alkynyl,” alone or in combination, refers to an optionallysubstituted straight-chain, optionally substituted branched-chain, orcyclic alkynyl hydrocarbon radical having one or more carbon-carbontriple-bonds and having from 2 to about 30 carbon atoms, more preferably2 to about 12 carbon atoms. The term also includes optionallysubstituted straight-chain or optionally substituted branched-chainhydrocarbon radicals having one or more carbon-carbon triple bonds andhaving from 2 to about 6 carbon atoms as well as those having from 2 toabout 4 carbon atoms. Examples of alkynyl radicals include ethynyl,propynyl, butynyl and the like.

The terms heteroalkyl, heteroalkenyl and heteroalkynyl includeoptionally substituted alkyl, alkenyl and alkynyl structures, asdescribed above, and which have one or more skeletal chain atomsselected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur,phosphorus or combinations thereof.

The term “carbon chain” may embrace any alkyl, alkenyl, alkynyl, orheteroalkyl, heteroalkenyl, or heteroalkynyl group, and may be linear,cyclic, or any combination thereof. If part of a linker and that linkercomprises one or more rings as part of the core backbone, for purposesof calculating chain length, the “chain” only includes those carbonatoms that compose the bottom or top of a given ring and not both, andwhere the top and bottom of the ring(s) are not equivalent in length,the shorter distance shall be used in determining chain length. If thechain contains heteroatoms as part of the backbone, those atoms are notcalculated as part of the carbon chain length.

The term “alkoxy,” alone or in combination, refers to an alkyl etherradical, alkyl-O—, wherein the term alkyl is defined as above. Examplesof alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “aryloxy,” alone or in combination, refers to an aryl etherradical wherein the term aryl is defined as below. Examples of aryloxyradicals include phenoxy, benzyloxy and the like.

The term “alkylthio,” alone or in combination, refers to an alkyl thioradical, alkyl-S—, wherein the term alkyl is defined as above.

The term “arylthio,” alone or in combination, refers to an aryl thioradical, aryl-S—, wherein the term aryl is defined as below.

The term “aryl,” alone or in combination, refers to an optionallysubstituted aromatic ring system. The term aryl includes monocyclicaromatic rings, polyaromatic rings and polycyclic aromatic ring systemscontaining from six to about twenty carbon atoms. The term aryl alsoincludes monocyclic aromatic rings, polyaromatic rings and polycyclicring systems containing from 6 to about 12 carbon atoms, as well asthose containing from 6 to about 10 carbon atoms. The polyaromatic andpolycyclic aromatic rings systems may contain from two to four rings.Examples of aryl groups include, without limitation, phenyl, biphenyl,naphthyl and anthryl ring systems.

The term “heteroaryl” refers to optionally substituted aromatic ringsystems containing from about five to about 20 skeletal ring atoms andhaving one or more heteroatoms such as, for example, oxygen, nitrogen,sulfur, selenium and phosphorus. The term heteroaryl also includesoptionally substituted aromatic ring systems having from 5 to about 12skeletal ring atoms, as well as those having from 5 to about 10 skeletalring atoms. The term heteroaryl may include five- or six-memberedheterocyclic rings, polycyclic heteroaromatic ring systems andpolyheteroaromatic ring systems where the ring system has two, three orfour rings. The terms heterocyclic, polycyclic heteroaromatic andpolyheteroaromatic include ring systems containing optionallysubstituted heteroaromatic rings having more than one heteroatom asdescribed above (e.g., a six membered ring with two nitrogens),including polyheterocyclic ring systems of from two to four rings. Theterm heteroaryl includes ring systems such as, for example, furanyl,benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkylpyrrolyl, pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imidazolyl, pyrazolyl,oxazolyl, benzothiophenyl, purinyl, indolizinyl, thienyl and the like,all optionally substituted.

The term “heteroarylalkyl” refers to a C1-C4 alkyl group containing aheteroaryl group, each of which may be optionally substituted.

The term “heteroarylthio” refers to the group —S-heteroaryl.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup. Suitable aralkyl groups include benzyl, picolyl, and the like,and may be optionally substituted.

The term “alkylaryl” refers to an aryl group substituted with an alkylgroup.

The term “amino” refers to —NRR′ where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl, all except H areoptionally substituted; and R and R′ can form a cyclic ring system.

The term “aminoalkyl” refers to the group —N(R)-alk where “alk” is analkyl group and R is selected from H, alkyl, aryl, and aralkyl.

The term “ureyl” or “urea” refers to the group R¹R²N—C(O)—NR³R⁴ whereR¹, R², R³ and R⁴ are independently selected from hydrogen, alkyl, aryl,aralkyl, all except H are optionally substituted; and R¹-R², R¹-R³R³-R⁴,or R²-R⁴ can form a cyclic ring system.

The term “carbamyl” or “carbamate” refers to the group R—O—C(O)—NR¹R²where R is alkyl, aryl, aralkyl, alkylaryl; and R¹ and R² areindependently selected from hydrogen, alkyl, aryl, aralkyl, all except Hare optionally substituted; and R¹ and R² can form a cyclic ring system.

The term “aralkyloxyalkyl-” refers to the group aryl-alk-O-alk-wherein“alk” is an alkylene group. “Lower aralkyloxyalkyl” refers to suchgroups where the alkylene groups are lower alkylene.

The term “perhalo” refers to groups wherein every C—H bond has beenreplaced with a C-halo bond on an aliphatic or aryl group. Suitableperhaloalkyl groups include —CF₃ and —CFCl₂.

The term “carbocycle” includes optionally substituted, saturated orunsaturated, three- to eight-membered cyclic structures in which all ofthe skeletal atoms are carbon.

The term “heterocyclic” refers to cyclic group of 3 to 10 atoms, morepreferably 3 to 6 atoms, containing at least one heteroatom, preferably1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, andnitrogen. Heterocyclic groups may be attached through a nitrogen orthrough a carbon atom in the ring. The heterocyclic groups includeunsaturated cyclic, fused cyclic and spirocyclic groups. Suitableheterocyclic groups include pyrrolidinyl, morpholino, andmorpholinoethyl. Heterocycles can be substituted or unsubstituted withone, two, three, four or five substituents independently selected fromamino, alkylamino, halogen, alkylacylamino, alkyl, aryl or alkoxy.

The term “sulfonyl” refers to —SO₂R where R is H, alkyl or aryl.

The term “sugar building block” refers to a saccharide group.

The term “saccharide group” refers to an oxidized, reduced orsubstituted saccharide monoradical covalently attached via any atom ofthe saccharide moiety, preferably via the aglycon carbon atom. Asaccharide refers to a carbohydrate which is a polyhydroxy aldehyde orketone, or derivative thereof, having the empirical formula (CH₂O)_(n)wherein n is a whole integer, typically greater than 3. Monosaccharides,or simple sugars, consist of a single polyhydroxy aldehyde or ketoneunit. Representative monosaccharides include, by way of illustrationonly, hexoses such as D-glucose, D-mannose, D-xylose, D-galactose,L-fucose, and the like; pentoses such as D-ribose or D-arabinose andketoses such as D-ribulose or D-fructose. Disaccharides contain twomonosaccharide units joined by a glycosidic linkage. Disaccharidesinclude, for example, sucrose, lactose, maltose, cellobiose, and thelike. Oligosaccharides typically contain from 2 to 10 monosaccharideunits joined by glycosidic linkages. Polysaccharides (glycans) typicallycontain more than 10 such units and include, but are not limited to,molecules such as heparin, heparan sulfate, chondroitin sulfate,dermatan sulfate and polysaccharide derivatives thereof. The term“sugar” generally refers to mono-, di- or oligosaccharides. A saccharidemay be substituted, for example, glucosamine, galactosamine,acetylglucose, acetylgalactose, N-acetylglucosamine,N-acetyl-galactosamine, galactosyl-N-acetylglucosamine,N-acetylneuraminic acid (sialic acid), etc., as well as sulfated andphosphorylated sugars. For the purposes of this definition, thesaccharides can be either in their open or preferably in their pyranoseform.

The term “amino-containing saccharide group” refers to a saccharidegroup having at least one amino substituent. Representativeamino-containing saccharides include mycaminose, desosamine,L-vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine,4-epi-vancosamine, acosamine, 3-amino-glucose, 4-deoxy-3-amino-glucose,actinosamine, daunosamine, 3-epi-daunosamine, ristosamine,N-methyl-D-glucamine and the like.

The term “halosugar” refers to a saccharide group having at least onehalogen substituent.

The term “acyloxy” refers to the ester group —OC(O)—R, where R is H,alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the alkyl, alkenyl,alkynyl and arylalkyl groups may be optionally substituted.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl orarylalkyl, wherein the alkyl, aryl and arylalkyl groups may beoptionally substituted.

The term “carboxamido” refers to

where each of R and R′ are independently selected from the groupconsisting of H, alkyl, aryl and arylalkyl, wherein the alkyl, aryl andarylalkyl groups may be optionally substituted.

The term “arylalkyl,” alone or in combination, refers to an alkylradical as defined above in which one H atom is replaced by an arylradical as defined above, such as, for example, benzyl, 2-phenylethyland the like.

The terms haloalkyl, haloalkenyl, haloalkenyl and haloalkoxy includealkyl, alkenyl, alkynyl and alkoxy structures, as described above, thatare substituted with one or more fluorines, chlorines, bromines oriodines, or with combinations thereof.

The terms cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl,alkenyl, haloalkyl and heteroalkyl include optionally substitutedcycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl,⁻alkenyl,haloalkyl and heteroalkyl groups.

The term “carbocycle” includes optionally substituted, saturated orunsaturated, three- to eight-membered cyclic structures in which all ofthe skeletal atoms are carbon.

The term “membered ring” can embrace any cyclic structure, includingcarbocycles and heterocycles as described above. The term “membered” ismeant to denote the number of skeletal atoms that constitute the ring.Thus, for example, pyridine, pyran, and thiopyran are 6 membered ringsand pyrrole, furan, and thiophene are 5 membered rings.

The term “acyl” includes alkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl substituents attached to a compound via a carbonylfunctionality (e.g., —CO-alkyl, —CO-aryl, —CO-arylalkyl or—CO-heteroarylalkyl, etc.).

The term “alkylacylamino” as used herein refers to an alkyl radicalappended to an acylamino group.

The term “acylamino” as used herein refers to an acyl radical appendedto an amino group.

The term “substituted heterocycle” or heterocyclic group” as used hereinrefers to any 3, or 4-membered ring containing a heteroatom selectedfrom nitrogen, oxygen, phosphorus and sulfur or a 5- or 6-membered ringcontaining from one to three heteroatoms selected from the groupconsisting of nitrogen, oxygen, phosphorus and sulfur; wherein the5-membered ring has 0-2 double bounds and the 6-membered ring has 0-3double bounds; wherein the nitrogen and sulfur atom maybe optionallyoxidized; wherein the nitrogen and sulfur heteroatoms maybe optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above. Heterocyclicscan be unsubstituted or monosubstituted or disubstituted withsubstituents independly selected from hydroxy, halo, oxo (C═O),alkylimino (RN=wherein R is a alkyl group), amino, alkylamino,dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, alkyl,cycloalkyl or haloalkyl. Examples of heterocyclics include: imidazolyl,pyridyl, piperazinyl, azetidinyl, thiazolyl and triazolyl.

“Optionally substituted” groups may be substituted or unsubstituted. Thesubstituents of an “optionally substituted” group may include, withoutlimitation, one or more substituents, more typically one to four,independently selected from the following groups or designated subsetsthereof: alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloalkenyl,haloalkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxy, aryloxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylthio,arylthio, heteroarylthio, oxo, carboxyesters, carboxamido, acyloxy, H,F, Cl, Br, I, CN, NO₂, NH₂, N₃, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃,OCF₃, CH₃, CF₃, C(O)CH₃, CO₂CH₃, CO₂H, C(O)NH₂, pyridinyl, thiophene,furanyl, indole, indazole, esters, amides, phosphonates, phosphates,phosphoramides, sulfonates, sulfates, sulfonamides, carbamates, ureas,thioureas, thioamides, thioalkyls. “Substituted aryl” and “substitutedheteroaryl” preferably refers to aryl and heteroaryl groups substitutedwith 1-3 substituents. Preferably these substituents are selected fromthe group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl,halo, hydroxy, and amino. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃).

The term “halogen” includes F, Cl, Br and I.

The term “isomeric mixture” means a mixture of two or moreconfigurationally distinct chemical species having the same chemicalformula. An isomeric mixture is genus comprising individual isomericspecies. Examples of isomeric mixtures include stereoisomers(enantiomers, diastereomers), regioisomers, as might result for examplefrom a pericyclic reaction. The compounds of the present inventioncomprise asymmetrically substituted carbon atoms. Such asymmetricallysubstituted carbon atoms can result in mixtures of stereoisomers at aparticular asymmetrically substituted carbon atom or a singlestereoisomer. As a result, racemic mixtures, mixtures of diastereomers,as well as single diastereomers of the compounds of the invention areincluded in the present invention. The terms “S” and “R” configuration,as used herein, are as defined by the IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,13-30.

The methods disclosed in the present invention may result in thepreparation of different regioisomers and or stereoisomers. This eventis not intended to lessen the usefulness of the presently disclosedmethods, rather isomeric mixtures may be more readily tested thanseparated isomeric species. Easily prepared mixtures of two or morestereoisomers or regioisomers may be separated if testing of isomericmixtures indicates that one or more active species is present.

Prodrugs

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates a biologically activecompound as a result of spontaneous chemical reaction(s),enzyme-catalyzed chemical reaction(s), and/or metabolic chemicalreaction(s), or a combination of each. Standard prodrugs are formedusing groups attached to functionality, e.g. HO—, HS—, HOOC—, R₂N—,associated with the drug, that cleave in vivo. Standard prodrugs includebut are not limited to carboxylate esters where the group is alkyl,aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters ofhydroxyl, thiol and amines where the group attached is an acyl group, analkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groupsillustrated are exemplary, not exhaustive, and one skilled in the artcould prepare other known varieties of prodrugs. Such prodrugs of thecompounds of Formula 1 and Formula 2 fall within the scope of thepresent invention. Prodrugs must undergo some form of a chemicaltransformation to produce the compound that is biologically active or isa precursor of the biologically active compound. In some cases, theprodrug is biologically active, usually less than the drug itself, andserves to improve drug efficacy or safety through improved oralbioavailability, pharmacodynamic half-life, etc. The biologically activecompounds include, but are not limited to antibiotic agents, anticanceragents, antiviral agents, and agents for treating gastric motilitydisorders.

Prodrugs contain a chemical moiety, e.g., an amide or phosphorus groupwhose function is to endow enhanced solubility and/or stability to theattached drug so that it can be effectively preserved/delivered to ahost. Once in the body, the prodrug is typically acted upon by an enzymein vivo, e.g., an esterase, amidase, or phosphatase, toliberate/generate the more pharmacologically active drug. Thisactivation may occur through the action of an endogenous host enzyme ora non-endogenous enzyme that is administered to the host preceding,following, or during administration of the prodrug. Prodrug use ingeneral is further discussed, e.g., in U.S. Pat. No. 5,627,165, as wellas in Pathak et al., Enzymic protecting group techniques in organicsynthesis, Stereosel. Biocatal. 775-797 (2000), and is otherwise wellknown in the art, although not to Applicants' knowledge using thespecific compounds and compositions claimed herein.

Ideally, the prodrug should be converted to the original drug as soon asthe goal is achieved, followed by the subsequent rapid elimination ofthe released derivatizing group. The term can also mean a nonspecificchemical approach to mask undesirable drug properties or improve drugdelivery. For example, many therapeutic drugs have undesirableproperties that may become pharmacological, pharmaceutical, orpharmacokinetic barriers in clinical drug application, such as low oraldrug absorption, lack of site specificity, chemical instability,toxicity, and poor patient acceptance (bad taste, odor, pain atinjection site, etc.). The prodrug approach, a chemical approach usingreversible derivatives, can be useful in the optimization of theclinical application of a drug.

Pharmaceutical Compositions/Formulations, Dosaging, and Modes ofAdministration

Those of ordinary skill in the art are familiar with formulation andadministration techniques, e.g., as discussed in Goodman and Gilman'sThe Pharmacological Basis of Therapeutics, current edition; PergamonPress; and Remington's Pharmaceutical Sciences (current edition.) MackPublishing Co., Easton, Pa. These techniques can be employed inappropriate aspects and embodiments of the invention.

The compounds utilized in the methods of the instant invention may beadministered either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

For example, the therapeutic or pharmaceutical compositions of theinvention can be administered locally to the area in need of treatment.This may be achieved by, for example, but not limited to, local infusionduring surgery, topical application, e.g., cream, ointment, injection,catheter, or implant, said implant made, e.g., out of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. The administration can also be by directinjection at the site (or former site) of a tumor or neoplastic orpre-neoplastic tissue.

Still further, the therapeutic or pharmaceutical composition can bedelivered in a vesicle, e.g., a liposome (see, for example, Langer,1990, Science, 249:1527-1533; Treat et al., 1989, Liposomes in theTherapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler(eds.), Liss, N.Y., pp. 353-365).

The pharmaceutical compositions used in the methods of the presentinvention can be delivered in a controlled release system. In oneembodiment, a pump may be used (see, Sefton, 1987, CRC Crit. Ref.Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery, 88:507; Saudek etal., 1989, N. Engl. J. Med., 321:574). Additionally, a controlledrelease system can be placed in proximity of the therapeutic target(see, Goodson, 1984, Medical Applications of Controlled Release, Vol. 2,pp. 115-138).

The pharmaceutical compositions used in the methods of the instantinvention can contain the active ingredient in a form suitable for oraluse, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients, which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,such as microcrystalline cellulose, sodium crosscarmellose, corn starch,or alginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to mask the taste of the drug ordelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, awater soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropyl cellulose, or a time delay material such asethyl cellulose, or cellulose acetate butyrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions can contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients can act as suspending agents and include, e.g., sodiumcarboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth andgum acacia; dispersing or wetting agents may be a naturally-occurringphosphatide, for example lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethylene-oxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant, e.g., butylated hydroxyanisol, alpha-tocopherol, orascorbic acid.

Dispersible powders and granules suitable- for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of antioxidant(s).

The pharmaceutical compositions used in the methods of the instantinvention may also be in the form of oil-in-water emulsions. The oilyphase may be a vegetable oil, for example olive oil or arachis oil, or amineral oil, for example liquid paraffin or mixtures of these. Suitableemulsifying agents may be naturally-occurring phosphatides, for examplesoy bean lecithin, and esters or partial esters derived from fatty acidsand hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of compositionsuitable for use as an inhalant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solution. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulsion.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butane-diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

The macrolides used in the methods of the present invention may also beadministered in the form of suppositories for rectal administration ofthe drug. These compositions can be prepared by mixing the inhibitorswith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Such materials include cocoabutter, glycerinated gelatin, hydrogenated vegetable oils, mixtures ofpolyethylene glycols of various molecular weights and fatty acid estersof polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing a macrolide can be used. As used herein, topicalapplication can include mouthwashes and gargles.

The compounds used in the methods of the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles and delivery devices, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

The methods and compounds of the instant invention may also be used inconjunction with other well known therapeutic agents that are selectedfor their particular usefulness against the condition that is beingtreated. For example, the instant compounds may be useful in combinationwith known anti-cancer and cytotoxic agents.

Preferably the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an amount that iseffective to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which ere less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The amount and frequency of administration of the compounds used in themethods of the present invention and, if applicable, otherchemotherapeutic agents will be regulated according to the judgment ofthe attending clinician (physician) considering such factors as age,condition and size of the patient as well as severity of the diseasebeing treated.

In general, compounds of the invention and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of the skilledclinician. The initial administration can be made according toestablished protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician. The particularchoice of compounds used will depend upon the diagnosis of the attendingphysicians and their judgment of the condition of the patient and theappropriate treatment protocol. The compounds may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, depending upon the natureof the proliferative disease, the condition of the patient, and theactual choice of compounds used.

The determination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

Representative compounds of the present invention of Formula 1 include,but are not limited to:

-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-2-hydroxy-propoxy)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-2-hydroxy-propionyl    ester)-3-oxo-erythronolide A, 11,12-carbamate;-   11-N[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-garosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-vancosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-amino-erythrosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-allofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altrofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin    n-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(4-deoxy-3-dimethylamino-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(4-deoxy-3-dimethylamino-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-6-O-phenylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-6-O-methylester-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-6-O-methylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-acetyl-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-0-acetyl-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A,11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-methylester-galactopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-phenylester-galactopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-threosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-amino-xylofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-(3-dimethylamino-xylopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-gulofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-guloyrannosyl)-3-oxo-erythronolide    A, 11 , 12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-6-O-acetylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-6-O-methylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate,-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-6-O-phenylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-acetylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-phenylester-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate,-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]thazol-1-yl]-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-glucopyranosyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotiazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-garosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-vancosaminyl-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-erythrosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-allofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altrofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-yl    methyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-threosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-xylofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-xylopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-gulofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-guloyrannosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactopyranosyl)-3-oxo-erythronolide    A,11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-phenylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyransyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-glucopyransyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-phenylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-yl    methyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-yl    methyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyransyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate,-   11-N-[4-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-phenylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-acetamido-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A,11,12-carbamate;-   11-N-[4-(3-acetamido-phenyl-1-yl    methyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(3-acetamido-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-4-deoxy-6-O-methylester-glucopyransyl)-3-oxo-2-fluoro-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-garosaminyl-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-vancosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-erythrosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altrofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronol    id e A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-threosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-xylofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-yl    methyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-xylopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-gulofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-guloyrannosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-mycaminosyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-garosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-vancosaminyl-3-oxo-erythronolide    A, ,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-erythrosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-ribopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-arabinopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-allofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altrofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-altropyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-glucopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-mannopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-threosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-xylofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-xylopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-lyxopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-gulofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo    [4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talofuranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-guloyrannosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-idopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-galactopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-(3-dimethylamino-talopyranosyl)-3-oxo-erythronolide    A, 11,12-carbamate;-   and their pharmaceutically acceptable salts, hydrates, solvates,    esters and prodrugs thereof.-   Representative compounds of the present invention of Formula 2    include, but are not limited to:-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-dasosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Imidazo[4,5-b]pyridin-3-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-dasosaminyl-2-fluoro-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-dasosaminyl-3-oxo-erythronolide    A, 11,12-carbamate,-   11-N-[4-(4-Benzimidazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-dasosaminyl-2-fluoro-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-{2-[4-(4-n-Pentylphenyl)-[1,2,3]triazol-1-yl]-6-O-methyl-5-O-dasosamnyl    3-oxo-erythronolide A, 11,12-cyclic carbonate.-   11-N-{2-[4-(4-n-Pentylphenyl)-[1,2,3]triazol-1-yl]-6-O-methyl-5-O-dasosamnyl    2-fluoro-3-oxo-erythronolide A, 11,12-cyclic carbonate.-   11-N-{4-[4-(2,6-Dichlorophenoxyoxymethyl)-[1,2,3]triazol-1-yl]-butyl}-6-O-methyl-5-O-dasosaminyl-3-oxo-erythronolide    A, 11,12-cyclic carbamate.-   11-N-{4-[4-(2,6-Dichlorophenoxyoxymethyl)-[1,2,3]triazol-1-yl]-butyl}-6-O-methyl-5-O-dasosaminyl-2-fluoro-3-oxo-erythronolide    A, 11,12-cyclic carbamate.-   11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl]-butyl}-5-O-desosaminyl-3-oxo-erythronolide    A,-11,12-cyclic carbamate.-   11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl]-butyl}-5-O-desosaminyl-2-fluoro-3-oxo-erythronolide    A,-11,12-cyclic carbamate.-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-desosaminyl-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-[4-(2-pyridyl-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-desosaminyl-2-fluoro-3-oxo-erythronolide    A, 11,12-carbamate;-   11-N-{4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl}-5-O-desosaminyl-3-oxo-erythronolide    A,-11,12-cyclic carbamate.-   11-N-{4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl}-5-O-desosaminyl-2-fluoro-3-oxo-erythronolide    A,-11,12-cyclic carbamate.

and their pharmaceutically acceptable salts, hydrates, solvates, estersand prodrugs thereof.

Preparation of Compounds

The compounds of Formula 1 may be prepared according to Schemes 1 belowand the description that follows. All other substituents, including X,Y, R₁, R₂, R₃, V and W are as defined in the Summary of the Inventionunless otherwise indicated.

The compounds of the invention are readily prepared. Referring to Scheme1, the starting compounds of Formulas 5 may be prepared fromErythromycin A, according to one or more methods familiar to thoseskilled in the art including the synthetic methods described by U.S.Pat. Nos. 5,635,485 and 6,028,181, both of which are hereby incorporatedby reference.

In step 1 of Scheme 1, the desosamine of Formula 5 is protected usingmethods know to those skilled in the art to provide a compound ofFormula 4; R can be ester protecting group but not limited to esterprotecting group. The cleavage of the desosamine sugar forms an aglyconecompound of Formula 3. In step2 of Scheme 1, the compound of Formula 3is functionalized to form a compound of Formula 1. Wherein R₁ isselected from cyclic and acyclic alkyl, cyclic and acyclicalkyl-hydroxyamine, aryl, aryl-hydroxyamine, cyclic and acyclic acyl,cyclic and acyclic acyl-hydroxyamine, heteroalkyl,heteroalkyl-hydroxyamine, heteroaryl, heteroaryl-hydroxyamine, acylaryl,acylaryl-hydroxyamine, acylheteroaryl, acylheteroaryl-hydroxyamine,alkylaryl, alkylaryl-hydroxyamine, alkylheteroaryl,alkyiheteroaryl-hydroxyamine, sulfonylalkyl, sulfonylalkyl-hydroxyamine,acylalkoxylsulfonylalkyl, acylalkoxylsulfonylalkyl-hydroxyamine;

or R₁ can be —C(O)-NR₄R₅, where R₄ and R₅ can be independently or takentogether as hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureaor carbamate and acceptable salts thereof;

or R₁ can also be a monosaccharide (including amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4-deoxy-3-amino-glucose derivatized at the C-6′ position), adisaccharide (including a mycaminose derivatized at the C-4′ positionwith another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6′position with another sugar), a trisaccharide (including aminosugars andhalosugars), chloramphenicol, clindamycin or their analogs; providedthat R₁ can not be desosamine.

Synthesis of the compounds of Formula 1 may comprise other steps inaddition to those shown in Scheme 1. For example, groups bonded to R₂may be modified following derivatization of C5 hydroxy group of formula3.

Compounds of Formula 2 comprise a heteroaromatic ring linked via aspacer to nitrogen at position 11 around a 14-membered macrolide core.The heteroaromatic ring and spacer are abbreviated “A-B-C”:

An “A-B-C” moiety may be appended to a macrolide scaffold using avariety of methods. Commercially available macrolides bear a number ofreactive functional groups, which may be further functionalized aftersuitable protection of other possible reactive sites. Macrolides thatbear nucleophilic functional groups (for example amines and hydroxylgroups) may be treated with an “E-B-T-C” fragment bearing at least onecomplimentary electrophilic group, E, that T represent 1,4-substituted1,2,3-triazole moiety. The terms “nucleophilic”, “nucleophile,”“electrophilic” and “electrophile” have their usual meanings familiar tosynthetic and/or physical organic chemistry.

Preferred electrophiles of the present invention are carbonelectrophiles. Examples of preferred carbon electrophiles include butare not limited to carbonyls (especially aldehydes and ketones), oximes,hydrazones, epoxides, aziridines, alkyl-, alkenyl-, and aryl halides,acyls, sulfonates (aryl, alkyl and the like). Other examples of carbonelectrophiles include unsaturated carbons electronically conjugated withelectron-withdrawing groups, examples being the β-carbon inα,β-unsaturated ketones or carbon atoms in fluorine substituted arylgroups. In general, carbon electrophiles are susceptible to attack bycomplementary nucleophiles wherein an attacking nucleophile brings anelectron pair to the carbon electrophile in order to form a new bondbetween the nucleophile and the electrophile.

Preferred nucleophiles suitable for coupling to carbon electrophilesinclude but are not limited to primary and secondary amines, thiols,thiolates, and thioethers, alcohols, alkoxides. These preferrednucleophiles, when used in conjunction with preferred carbonelectrophiles, typically generate heteroatom linkages (C-X-C) between ascaffold and a linker group. Nucleophilic attack by the macrolidenucleophile on a suitably substituted heteroaromatic substrate “B-T-C”bearing a functional group “E”, which contains an electrophilic carbonor sulfur atom, can thus unite the two through the formation of linker“A” (Scheme 2).

Alternatively, the fragment “A-B-T-C” can be attached to a macrolidescaffold in a stepwise manner such as described below in examples 1-5.Here the heterocyclic ring “T” is a 1,4-substituted 1,2,3-triazoleprepared using a Huisgen cyclization, which constitutes the final stepof each synthesis. The copper catalyzed Huisgen cyclization has beenshown to unite azides and terminal acetylenes regiospecifically to giveexclusively 1,4-disubstituted [1,2,3]-triazoles (Tornøe et al., J. Org.Chem., 2002, 67, 3057) and this observation was confirmed using NOEexperiments carried out on model compounds. Commercially availablemacrolides were suitably protected and then modified by the attachmentof either an azide or an alkyne functional group through a linker orspacer “A-B”. The activated macrolides were then coupled with thefragment “C” which bears the complimentary functional group. Thereactions were carried out either solvent-free, in water or in anorganic solvent such as acetonitrile or toluene. The reactions werecarried out at temperatures ranging from 20 to 80° C. The reaction couldbe promoted with the use of a catalyst, including but not limited to atransition metal halide (MX_(n)) (Scheme 3).

The term “scaffold” refers to a molecule that provides a molecularframework on which to append another chemical moiety or functionalgroup. An antibiotic scaffold is a scaffold having recognized usefulnessas an antibiotic. Appending chemical moieties to an antibiotic scaffoldmay beneficially alter a number of properties of an antibioticincluding, but not limited to, absorption, distribution, metabolism,excretion and toxicity, and efficacy.

The term “unsaturated moiety” refers in general to a moiety comprisingone or more π-bonds. Examples of such moieties are optionallysubstituted alkenes, alkynes, and nitriles. Unsaturated moieties undergopericyclic reactions with complimentary dienes, heterodienes, and1,3-dipoles resulting in the formation of 5 and 6-membered ringcompounds. 1,3-Dipoles and dienes may themselves be part of anopen-chain framework, or part of a ring system, with the exception thatthey may not be frozen into a transoid configuration.

The term “pericyclic reaction” refers to a family of chemical reactionscharacterized by bonding changes taking place through reorganization ofelectron pairs within a closed loop of interacting orbitals. Bondingchanges in pericyclic reactions are typically, but not necessarilyconcerted, that is, bonds break and form simultaneously rather than intwo or more steps. Preferred types of pericyclic reactions include butare not limited to cycloaddition reactions. A cycloaddition reaction isa reaction in which two or more molecules condense to form a ring bytransferring electrons from π-bonds to new σ-bonds. Examples of suchreactions are Huisgen cycloadditions, Diels-Alder and hetero Diels-Aldercycloadditions. A preferred type of cycloaddition reaction according toone embodiment of the invention is a Huisgen cyclization. A Huisgencycloaddition involves the addition of an unsaturated moiety to a 1,3dipole, as for example shown schematically below:

Triazoles result when azides add to triple bonds in a Huisgencycloaddition. A Huisgen cycloaddition is one example of a group ofreactions in which five-membered heterocyclic compounds are prepared byaddition of 1,3-dipolar compounds to an unsaturated (usually double ortriple) bond, the latter also known as a 1,3-dipolaraphile.

When two molecules react to form a cycloadduct, mixtures may result.Obtaining one or more desired cycloadduct when several are theoreticallypossible is known as stereocontrol. When an unsymmetrical 1,3-dipoleadds to an unsymmetrical dipolarophile, there are two possible products(not counting stereoisomers). Although mixtures are often obtained, onemay predominate. This regioselectivity may often be explained viatheoretical and or calculational considerations.

The invention will be further illustrated by reference to the followingnon-limiting Examples.

EXAMPLE 1 11-N-(4-Azido-butyl)-6-O-methyl-5-OH-3-oxo-erythronolide A,11,12-carbamate.

DMSO (0.313 mL, 4.4 mmol) was added dropwise to a solution of oxalylchloride (2M solution in CH₂Cl₂, 1.47 mL, 2.94 mmol) and CH₂Cl₂ (10 mL)at −65° C. After 10 min, a solution of11-N-(4-Azido-butyl)-6-O-methyl-5-desosaminyl-3-hydroxyl-erythronolideA, 11,12-carbamate (0.6 g, 0.84 mmol) and CH₂Cl₂ (10 mL) was slowlyadded and the reaction mixture was gradually allowed to warm to 50° C.After 30 min, Et₃N (1.03 mL, 7.35 mmol) was added and the reactionmixture was slowly allowed to warm to rt. Saturated aqueous NaHCO₃solution (10 mL) was added and the resulting layers were separated. Theaqueous layer was extracted with CH₂Cl₂ (50 mL) and the combined organiclayers were dried with Na₂SO₄ and concentrated. The resulting yellowsolid was dissolved in MeOH (50 mL) and solution was allowed to stand at45° C. under nitrogen protection for 24 h. Concentration followed bysilica gel chromatography (5:1, Tol:Acetone) afforded 271 mg (57%) of11-N-(4-azido-butyl)-6-O-methyl-5-OH-3-oxo-erythronolide A,11,12-carbamate as a white solid. MS: C₂₇H₄₄N₄O₈ calculated M⁺=552.3,Found: M+H⁺=553.3.

EXAMPLE 211-N-(4-Azido-butyl)-2-Fluoro-6-O-methyl-5-OH-3-oxo-erythronolide A,11,12-carbamate.

DMSO (0.110 mL, 1.54 mmol) was added dropwise to a solution of oxalylchloride (2M solution in CH₂Cl₂, 0.51 mL, 1.026 mmol) and CH₂Cl₂ (5 mL)at −65° C. After 10 min, a solution of11-N-(4-Azido-butyl)-2-fluoro-6-O-methyl-5-desosaminyl-3-hydroxyl-erythronolideA, 11,12-carbamate (0.37 g, 0.51 mmol) and CH₂Cl₂ (3 mL) was slowlyadded and the reaction mixture was gradually allowed to warm to −50° C.After 30 min, Et₃N (0.36 mL, 2.56 mmol) was added and the reactionmixture was slowly allowed to warm to rt. Saturated aqueous NaHCO₃solution (10 mL) was added and the resulting layers were separated. Theaqueous layer was extracted with CH₂Cl₂ (50 mL) and the combined organiclayers were dried with Na₂SO₄ and concentrated. The resulting yellowsolid was dissolved in MeOH (50 mL) and solution was allowed to stand at45° C. under nitrogen protection for 24 h. Concentration followed bysilica gel chromatography (5:1, Tol:Acetone) afforded 157 mg (54%) of11-N-(4-azido-butyI)-2-fluoro-6-O-methyl-5-OH-3-oxo-erythronolide A,11,12-carbamate as a white solid. MS: C₂₇H₄₃N₄FO₈ calculated M⁺=570.3,Found: M Na⁺=593.3.

EXAMPLE 311-N-(4-Azido-butyl)-6-O-methyl-5-(2,6-dibenzoyl-3H-Fmoc-4-deoxy-glucopyranosyl)-3-oxo-erythronolide11,12-carbamate.

N-lodosuccinimide (0.630 g, 2.8 mmol) was added to a mixture of11-N-(4-Azido-butyl)-6-O-methyl-5-OH-3-oxo-erythronolide A,11,12-carbamate (1 g, 1.8 mmol),2,6-dibenzoyl-3-N-Fmoc-4-deoxy-1-thio-D-glucopyranoside(1.64 mg, 2.35mmol), molecular sieves (0.5 g), and CH₂Cl₂ (24 mL) at −78° C. After 10min, AgOTf (0.84 g, 3.24 mmol) and 2,6-Di-tert-butyl-pyridine (0.68g,3.56 mmol) were added and the mixture was gradually allowed to warm tort. After 6 h, a 1:1 mixture of saturated aqueous NaHCO₃ and Na₂SO₃ (100mL) was added and the mixture was diluted with CH₂Cl₂ (250 mL) and theresulting layers were separated. The organic layer was dried with Na₂SO₄and concentrated. Purification by silica gel chromatography (10:1,Toluene:Acetone) afforded 1.35 g of compound 3 as a white film. MS:C₆₂H₇₃N₅O₁₅ calculated M⁺=1127.51, Found: M+Na⁺=1150.5.

EXAMPLE 411-N-(4-Azido-butyl)-6-O-methyl-5-(3-dimethylamine-4-deoxy-6-benzoy-glucopyranosyl)-2-fluoro-3-oxo-erythronolideA, 11,12-carbamate.

Piperidine (0.2 mL,10% in DMF) was added to11-N-(4-Azido-butyl)-6-O-methyl-5-(2,6-dibenzoyl-3N-Fmoc-4-deoxy-glucopyranosyl)-2-fluoro-3-oxo-erythronolideA, 11,12-carbamate (27 mg, 0.024 mmol), at room temperature. After 10min, the reaction mixture were concentrated in vacuum and re-constitutedwith THF (1 mL). To the above solution, formaldehyde (37% aqueoussolution, 0.05 mL, 0.67 mmol) and Sodium triacetoxyborohydride (50 mg,0.22 mmol) were added at room temperature. After 2 hour of stirring, thereaction mixture was diluted with 1:1 ratio of saturated aqueousammonium chloride and dichloromethane (20 mL). The organic layer wasseparated and dried with Na₂SO₄ and concentrated to give a while film.The intermediate was dissolved in methanol and stirred for 18 hour atrt. Concentration of the above reaction mixture follows by purificationwith silica gel chromatography (10:1, Toluene:Acetone) afforded 10 mg oftitle compound as a white film. MS: C₄₂H₆₂FN₅O₁₂, calculated M⁺=847.44,Found: M +H⁺=848.5

EXAMPLE 5 OP-1356:11-N-{4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl}-5-(3-dimethylamine-4-deoxy-6-O-acetyl-glucopyranosyl)-3-oxo-2-fluoro-erythronolideA,-11,12-cyclic carbamate.

A mixture of11-N-(4-Azido-butyl)-6-O-methyl-5-(3-dimethylamine-4-deoxy-6-O-acetyl-glucopyranosyl)-2-fluoro-3-oxo-erythronolideA, 11,12-carbamate (15 mg, 0.019 mmol), 6-Ethynyl-pyridin-2-ylamine (4.7mg, 0.4 mmol), Cul (1 mg, 0.005 mmol), and toluene (0.2 mL) was heatedto 70° C. After 16 h, the mixture was concentrated and directlysubjected to silica gel chromatography (9:1, Chloroform: Methanol plus1% ammonium hydroxide) to give 14 mg of the desired compound OP-1356.MS: C₄₄H₆₆FN₇O₁₂ calculated M⁺=903.5, Found: M+H⁺=904.5.

EXAMPLE 611-N-(4-Azido-butyl)-6-O-methyl-5-(2-acetyl-desosamynyl)-3-oxo-2-fluoro-erythronolideA, 11,12-carbamate.

To a solution of11-N-(4-Azido-butyl)-6-O-methyl-5-(2-acetyl-desosamynyl)-3-oxo-erythronolideA, 11,12-carbamate (500 mg, 0.66 mmol) in THF (8 mL), t-BuOK (0.73 mL,1.0 M, 0.73 mmol) followed by N-Fluorobenzene-sulfonimide (211mg, 0.66mmol) were added dropwise at 0° C. After 40 min., the mixture wasquenched with water (2 mL) follow by dilution of dichloromethane (200mL). The organic layer were separated and washed with water (20 mL×2).Upon concentration of the organic layer gave 482 mg of product. MS:C₃₇H₆₀FN₅O₁₁ calculated M⁺=769.43, Found: M+H⁺=770.5.

EXAMPLE 7 OP-1068:11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]triazol-1-yl]-butyl}-5-desosaminyl-3-oxo-2-fluoro-erythronolideA,-11,12-cyclic carbamate.

A mixture of11-N-(4-Azido-butyl)-6-O-methyl-5-desosamynyl-3-oxo-2-fluoro-erythronolideA, 11,12-carbamate (17 mg, 0.023 mmol), 3-Ethynyl-phenylamine (5.4 mg,0.046 mmol), Cul (1 mg, 0.005 mmol), and toluene (0.2 mL) was heated to70° C. After 16 h, the mixture was concentrated and directly subjectedto silica gel chromatography (9:1, Chloroform: Methanol plus 1% ammoniumhydroxide) to give 17 mg of the desired compound, OP1068. MSC₄₃H₆₅FN₆O₁₀ calculated M⁺=844.47, Found: M+H⁺=845.5

EXAMPLE 8OP-1357:11-N-{4-[4-(6-Amino-pyridin-2-yl)-[1,2,3]triazol-1-yl]-butyl}-5-desosaminyl-3-oxo-2-fluoro-erythronolideA,-11,12-cyclic carbamate.

A mixture of1-N-(4-Azido-butyl)-6-O-methyl-5-desosamynyl-3-oxo-2-fluoro-erythronolideA, 11,12-carbamate (15 mg, 0.02 mmol), 6-Ethynyl-pyridin-2-ylamine (4.7mg, 0.4 mmol), Cul (1 mg, 0.005 mmol), and toluene (0.2 mL) was heatedto 70° C. After 16 h, the mixture was concentrated and directlysubjected to silica gel chromatography (9:1, Chloroform: Methanol plus1% ammonium hydroxide) to give 14 mg of the desired compound OP1357. MS:C₄₂H₆₄FN₇O₁₀ calculated M⁺=845.5, Found: M+H⁺=846.5.

EXAMPLE 911-N-(4-Azido-butyl)-6-O-methyl-5-(2,4-dibenzoyl-3N-Fmoc-mycaminosyl)-3-oxo-erythronolideA, 11,12-carbamate.

N-lodosuccinimide (162 mg, 0.72 mmol) was added to a mixture of11-N-(4-Azido-butyl)-6-O-methyl-5-OH-3-oxo-erythronolide A,1¹1,12-carbamate (200 mg, 0.36 mmol),2,6-dibenzoyl-3-N-Fmoc-1-thiomycaminoside (378 mg, 0.54 mmol), molecularsieves (0.2 g), and CH₂Cl₂ (2.5 mL) at −78° C. After 10 min, AgOTf (224mg, 0.86 mmol) and 2,6-Di-tert-butyl-pyridine (0.21 mL, 0.95 mmol) wereadded and the mixture was gradually allowed to warm to rt. After 18 h, a1:1 mixture of saturated aqueous NaHCO₃ and Na₂SO₃ (100 mL) was addedand the mixture was diluted with CH₂Cl₂ (250 mL) and the resultinglayers were separated. The organic layer was dried with Na₂SO₄ andconcentrated. Purification by silica gel chromatography (10:1,Toluene:Acetone) afforded 293 mg of title compound as a white film. MS:C₆₂H₇₃N₅O₁₅ calculated M⁺=1127.51, Found: M+Na⁺=1150.5.

EXAMPLE 1011-N-(4-Azido-butyl)-6-O-methyl-5-mycaminosyl-3-oxo-erythronolide A,11,12-carbamate.

Piperidine (0.2 mL,10% in DMF) was added to11-N-(4-Azido-butyl)-6-O-methyl-5-(2,4-dibenzoyl-3N-Fmoc-mycaminosyl)-3-oxo-erythronolideA, 11,12-carbamate (30 mg, 0.026 mmol), at room temperature. After 10min, the reaction mixture were concentrated in vacuum and re-constitutedwith THF (1 mL). To the above solution, formaldehyde (37% aqueoussolution, 0.05 mL, 0.67 mmol) and Sodium triacetoxyborohydride (50 mg,0.22 mmol) were added at room temperature. After 2 hour of stirring, thereaction mixture was diluted with 1:1 ratio of saturated aqueousammonium chloride and dichloromethane (20 mL). The organic layer wasseparated and dried with Na₂SO₄ and concentrated to give a while film.The intermediate was dissolved in methanol and stirred for 18 hour atrt. Concentration of the above reaction mixture follows by purificationwith silica gel chromatography (10:1, Toluene:Acetone) afforded 9 mg oftitle compound as a white film. MS: C₃₅H₅₉N₅O₁₁, calculated M⁺=725.4,Found: M+H⁺=726.5

EXAMPLE 11 OP-1007:11-N-[4-(4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)-butyl]-6-O-methyl-5-O-dasosaminyl-3-oxo-erythronolideA, 11,12-carbamate.

A mixture of11-N-(4-Azido-butyl)-6-O-methyl-5-O-desosaminyl-3-oxo-erythronolide A,11,12-carbamate (3 mg, 0.0039 mmol), 1-Prop-2-ynyl-1H-benzotriazole (3mg, 0.4 mmol), Cul (1 mg, 0.005 mmol), and toluene (0.2 mL) was heatedto 80° C. After 16 h, the mixture was concentrated and directlysubjected to silica gel chromatography (9:1, Chloroform: Methanol plus1% ammonium hydroxide) to give 3 mg of the desired compound OP-1007. MS:C₄₄H₆₆N₈O₁₀ calculated M⁺=866.5, Found: M+H⁺867.5.

EXAMPLE 12 OP-1071:11-N-[4-(4-Benzotriazol-1-ylmethyl-[1,2,3]triazol-1-yl)butyl]-6-O-methyl-5-mycaminosyl-3-oxo-erythronolide A, 11,12-carbamate.

A mixture of11-N-(4-Azido-butyl)-6-O-methyl-5-mycaminosyl-3-oxo-erythronolide A,11,12-carbamate (3 mg, 0.004 mmol), 1-Prop-2-ynyl-1H-benzotriazole (3mg, 0.4 mmol), Cul (1 mg, 0.005 mmol), and toluene (0.2 mL) was heatedto 80° C. After 16 h, the mixture was concentrated and directlysubjected to silica gel chromatography (9:1, Chloroform: Methanol plus1% ammonium hydroxide) to give 3 mg of the desired compound OP-1071. MS:C₄₄H₆₆N₈O₁₁ calculated M⁺=882.5, Found: M +H⁺=883.5.

EXAMPLE 1311-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-OH-3-oxo-erythronolideA, 11,12-carbamate.

DMSO (0.22 mL, 3.0 mmol) was added dropwise to a solution of oxalylchloride (2M solution in CH₂Cl₂, 1.4 mL, 2.7 mmol) and CH₂Cl₂ (6 mL) at−70° C. After 10 min, a solution of Telithromycin (1.0 g, 1.2 mmol) andCH₂Cl₂ (6 mL) was slowly added and the reaction mixture was graduallyallowed to warm to −50° C. After 30 min, Et₃N (0.9 mL, 6 mmol) was addedand the reaction mixture was slowly allowed to warm to rt. Saturatedaqueous NaHCO₃ solution (10 mL) was added and the resulting layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (50 mL) and thecombined organic layers were dried with Na₂SO₄ and concentrated. Theresulting yellow solid was dissolved in MeOH (50 mL) and solution wasallowed to stand at rt overnight. Concentration followed by silica gelchromatography (5:5:O.5:O.1, Tol:Acetone:MeOH:Et₃N) afforded 350 mg(44%) of11-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-OH-3-oxo-erythronolideA, 11,12-carbamate as a white solid. MS: C₃₅H₅₀N₄O₈ calculated M⁺=654.8,Found: M+H⁺=655.4.

EXAMPLE 14OP-1086:11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-O-(N-t-butylcarbonate-N,O-isopropylideneisoserinate)-3-oxo-erythronolide A, 11,12-carbamate.

11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-OH-3-erythronolideA, 11,12-carbamate (56.7 mg, 86.6 mmol) was taken up in 1 mL ofdichloromethane. To the solution was added 60 mg ofN-t-butylcarbonate-N,O-isopropylidene isoserine triethylamine salt (173mmol) followed by 33.1 mg of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mmol)and 42.2 mg of 4-(dimethylamino)pyridine (346 mmol). The reaction wasallowed to stir overnight and was incomplete mass spectroscopy. Anadditionally 8 equivalents of N-t-butylcarbonate-N,O-isopropylideneisoserine triethylamine salt and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride were addedand the reaction was complete within 1 hour. The solution was quenchedwith saturated sodium bicarbonate solution and extracted with three 10mL-portions of dichloromethane. The organic layers were combined anddried (MgSO₄). The solution was concentrated under diminished pressureand purified by flash column chromatography on silica (10 g). The columnwas eluted with 97.5:2.5 (dichloromethane-methanol) to afford thecompound as a colorless foam and a 1:1 mixture of diastereomers: yield45 mg (59%); silica gel TLC R_(f) 0.78 (9:1:0.1chloroform-methanol-ammonium hydroxide); ¹H NMR (400 MHz, CDCl₃) δ0.81-1.99 (m, 47H), 2.55-3.24 (m, 5H), 3.39-4.08 (m, 7H), 4.60 (m, 1H)4.92 (m, 1/2H), 5.03 (m, 1/2H), 5.15 (m, 1/H), 5.74 (1/2H, dd, J=10, 4.5Hz), 7.30 (m, 1H), 7.34 (s, 1/2H), 7.39 (s, 1/2H), 7.55 (s, 1/2H), 7.60(s,_1/2 H), 8.45 (m, 1H), 8.10 (s, 1H), 8.96 (s, 1H); ¹³C NMR (100 MHz,CDCl₃) δ 10.51, 10.69, 13.81, 13.85, 14.20, 14.79, 15.89, 16.58, 18.35,19.12, 19.40, 22.17, 24.22, 28.35, 28.40, 28.57, 28.76, 38.51, 38.82,39.11, 39.47, 42.43, 42.51, 44.57, 45.43, 46.80, 46.87, 48.02, 50.19,50.62, 51.45, 58.69, 60.08, 58.69, 60.08, 75.78, 77.36, 77.58, 82.06,82.18, 115.56, 123.54, 131.91, 131.99, 137.55, 138.78, 143.47, 145.39,147.58, 157.20, 169.03, 169.42, 200.90, 215.45; MS: C₄₆H₆₇N₅O₁₂calculated M⁺=881.5, Found: M+H⁺=882.4.

EXAMPLE 1511-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-O-N-dimethylisoserinate)-3-oxo-erythronolideA, 11,12-carbamate.

Part I,11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-O-(N-t-butyl-carbonate-N,O-isopropylideneisoserinate)-3-erythronolide A, 11,12-carbamate (25.0 mg, 28.3 mmol) wastaken up in 200 mL of ice cold 65% aqueous trifluoroacetic acid. Thesolution was stirred 1 hour at 0° C. and concentrated to dryness; MS:C₄₃H₆₃N₅O₁₂ calculated M⁺=841.5, Found: M+H⁺=842.4.

Part II, the vacuum dried crude from part I, in the same flask was takenup in 200 mL of cold 1:1 dimethylsulfide-trifluoroacetic acid. Thesolution was stirred at stirred 1 hour at 0° C. and concentrated todryness; MS: C₃₈H₅₅N₅O₁₀ calculated M⁺=741.4, Found: M+H⁺=742.4.

Part III, 17 mg of11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-O-isoserinate-3-erythronolideA, 11,12-carbamate (19.8 mmol) from part II, was taken up in 300 mL oftetrahydrofuran. To the solution was added 15.4 mL of 37% aqueousformaldehyde (198 mmol) and 12.6 mg sodium triacetoxyborohydride (59.6mmol). The solution was allowed to stir 1 hour and was concentrated todryness. The residue was purified by flash column chromatography onsilica (4 g). The column was eluted with 95:5:0.1(dichloromethane-methanol-ammonium hydroxide) to afford the compound asa colorless foam and a 1:1 mixture of diastereomers: yield 7.5 mg (49%);silica gel TLC R_(f) 0.52 (4:1 hexanes-ethyl acetate); ¹H NMR (400 MHz,CDCl₃) δ 0.82-0.88 (m, 4H), 1.01 (m, 4H), 1.22 (m, 10H), 1.40 (m, 3H),1.49 (s, 3H), 1.62-1.68 (m, 4H), 1.88-1.99 (m, 4H), 2.57-2.65 (m, 4H),2.91 (m, 3H), 2.93 (m, 3H), 3.36 (m, 2H), 3.50 (m, 1H), 3.65-3.82 (m,4H), 4.03 (t, 2H, J=7.0 Hz), 4.68 (m, 1H), 4.90 (d, 1H, J=10.5 Hz), 5.68(d, 1H, J=10 Hz), 7.27 (m, 1H), 7.39 (s, 1H), 7.61 (s, 1H), 8.18 (m,1H), 8.49 (bs, 1H), 8.99 (bs, 1H); MS: C₄₀H₅₉N₅O₁₀ calculated M⁺=769.4,Found: M+H⁺=770.4.

EXAMPLE 1611-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-O-allyl-3-oxo-erythronolideA, 11,12-carbamate.

11-N-[4-(4-Pyridin-3-yl-imidazol-1-yl-butyl]-6-O-methyl-5-OH-3-erythronolideA, 11,12-carbamate(1 eq.), allyl t-butyl carbonate (1.5 eq.), palladiumacetate (0.005 eq.), and triphenylphosphine (0.043 eq.) were taken up indry THF. The reaction mixture was purged with N₂ before the reactionmixture was heated to reflux. The reaction was allowed to reflux untilcomplete by TLC (95:0.5:0.05 of CHCl₃:MeOH:NH₄OH), approximately 24hours. The mixture was concentrated to dryness and purified by columnchromatography (15% 9:1:0.1 of CHCl₃:MeOH:NH₄OH, 85% CHCI₃). MS:C₃₅H₅₄N₄O₈ calculated M⁺=694.4, Found: M+H⁺=695.4.

EXAMPLE 17

Antibacterial activity of the novel Formula 1 and Formula 2 compoundsand their pharmaceutically acceptable addition salts with organic andinorganic acids was determined against a series of microorganisms fromthe American Type Culture Collection (ATCC) and clinical Streptococcussp isolates. The ATCC strains included: Staphylococcus aureus,Enterococcus faecium, Klebsiella pneumoniae, Escherichia coli,Salmonella typhimurium, Streptococcus pneumoniae, Streptococcuspyogenes, and Haemophilus influenzae. The clinical strains includedmacrolide resistant Streptococcus sp. with either Erm or MefA resistancemechanisms. The clinical isolates were identified using the APIbiochemical identification system (BioMerieux).

Antimicrobial susceptibility testing was performed according torecommendations by the National Committee for Clinical LaboratoryStandards (NCCLS M100-S12, M7-A5). Briefly, two fold dilutions ofcompounds were made in microtiter plates. Each well of the microtiterplate was inoculated with test microorganisms at a final density 5×10⁵colony forming units(cfu)/mL. The microtiter plates were incubated at35° C. under aerobic conditions, except for H. influenzae and S.pyogenes which were incubated at 5%' CO₂. The minimal inhibitoryconcentration (MIC) was defined as the lowest concentration of compoundthat inhibited growth. The results of represented examples of thisinvention on standard test microorganisms and clinical isolates incomparison with azithromycin and telithromycin are shown in Table 1 andTable 2.

TABLE 1 Antibacterial in vitro activity of OP1007 (Example 11), OP1071(Example 12) and OP1086 (Example 14) in comparison to Azithromycin andTelithromycin (nd = not determined). S. aureus ATCC 29213 E. faecium E.Coli S. Typhimurium S. pneumoniae (MSSA) ATCC K. Pneumonia ATCC ATCCATCC ID MLS-S 19434 13883 25922 14028 49619 OP- MIC (mcg/mL) 1007<=0.125 <=0.125 32 64 8 <=0.125 1071 0.25 <=0.125 >64 >64 >64 <=0.1251086 4 4 >64 >64 >64 Nd Azithromycin 1 4 8 8 4 <=0.125 Telithomycin<=0.125 <=0.125 16 16 4 <=0.125 S. pyogenes S. aureus H. influenzae ATCCS. pneumoniae S. pneumoniae MRSA ATCC ID 19615 163 (Mefa) 303 (ErmB)33591 49247 OP- MIC (mcg/mL) 1007 <=0.125 <=0.125 >64 >64 0.5 1071<=0.125 0.5 >64 >64 2 1086 32 <=0.125 0.25 >64 >64 Azithromycin 1<=0.125 0.5 >64 2 Telithomycin <=0.125 <=0.125 <=0.125 >64 2

It is noteworthy that compounds of the present invention showsignificant improvement in inhibitory activity against telithromycinresistant isolates pathogens, Streptococcus pyogenes while they stillmaintains their similar activity against other pathogens (See Table 2).

TABLE 2 Antibacterial in vitro activity of novel ketolides in comparisonto Telithromycin (nd = not determined). S. pneumoniae ATCC S. pneumoniaeS. pneumoniae S. pneumoniae S. pneumoniae ID 49619 ErmB 303 163 (Mef A)3773 (ErmB) 5032 OP- MIC (mcg/mL) 1068 <=0.125 <=0.125 <=0.125 0.5, 10.5 1274 <=0.125 <=0.125 <=0.125 4 0.25 1313 <=0.125 <=0.125 <=0.125 10.5 1318 <=0.125 <=0.125 <=0.125 2 2 1356 <=0.125 <=0.125 <=0.125 0.5 11357 <=0.125 <=0.125 <=0.125 1 1 Teli <=0.125 <=0.125 <=0.125 1 1 H.influenzae S. pyogenes S. pyogenes S. pyogenes S. pyogenes ATCC ID 17211850 3029 3262 49247 OP- MIC (mcg/mL) 1068 0.5 <=0.125 <=0.125 0.5 2, 41274 16 0.25 <=0.125 0.5 8 1313 2 0.25 0.25 2 2 1318 1 0.25 nd 1 8 13564 0.25 1 4 1 1357 2 0.25 1 1 4 Teli 64 8 16 32 4

It is to be understood that the above description is intended to beillustrative and not restrictive. Many embodiments will be apparent tothose of in the art upon reviewing the above description. The scope ofthe invention should therefore, be determined not with reference to theabove description, but should instead be determined with reference tothe appended claims, along with the full scope of equivalents to whichsuch claims are entitled. The disclosures of all articles andreferences, including patent publications, are incorporated herein byreference.

1.-17. (canceled)
 18. A compound of the formula

or a salt thereof, wherein: Macrolide is an antibiotic or antibiotic scaffold; A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)₂NH, or C(O)NHS(O)₂; B is alkylene or unsaturated alkylene; and C is hydrogen; or C is hydroxy, alkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, or heteroarylheteroalkyl, each of which is optionally substituted.
 19. The compound of claim 18 wherein A is CH₂.
 20. The compound of claim 18 wherein B is (CH₂)_(n), where n is 0 to
 10. 21. The compound of claim 18 wherein B is (CH₂)_(n), where n is 1 to
 10. 22. The compound of claim 18 wherein B is (CH₂)_(n), where n is 3 to
 5. 23. The compound of claim 18 wherein B is (CH₂)₃.
 24. The compound of claim 18 wherein C is optionally substituted aryl.
 25. The compound of claim 18 wherein C is optionally substituted arylalkyl.
 26. A process for preparing a compound of the formula

or a salt thereof; the process comprising contacting a compound of the formula Macrolide-A-B-N₃ with a compound of the formula H═C and a copper catalyst; wherein Macrolide is an antibiotic or antibiotic scaffold; A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)₂NH, or C(O)NHS(O)₂; B is alkylene or unsaturated alkylene; and C is hydrogen; or C is hydroxy, alkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, or heteroarylheteroalkyl, each of which is optionally substituted.
 27. A process for preparing a compound of the formula

or a salt thereof; the process comprising contacting a compound of the formula Macrolide-A-B-H with a compound of the formula N₃—C and a copper catalyst; wherein Macrolide is an antibiotic or antibiotic scaffold; A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)₂NH, or C(O)NHS(O)₂; B is alkylene or unsaturated alkylene; and C is hydrogen; or C is hydroxy, alkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, or heteroarylheteroalkyl, each of which is optionally substituted. 